Middle-aged men and women suffering from depression may be more susceptible to dementia down the line, a recent study reports in the Archives of General Psychiatry.

Previous studies have linked depression in older adults with dementia and Alzheimer’s disease, but it has never been clear which came first: was depression a risk factor for dementia or an early symptom? The new study sought to look at depression at younger ages to see if the condition preceded memory decline.

“We wanted to look at whether depression is truly causal, or if it’s a reaction to cognitive impairment, or if the changes in the brain are causing both depression and cognitive decline at the same time,” says study author Dr. Deborah Barnes of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center.

To clarify the timing of depression and memory loss onset, the research team conducted a life-course study that first looked at the incidence of depression in midlife. The team included more than 13,000 people ages 40 to 55 who were part of the Kaiser Permanente Medical Care Program of Northern California and participated in a health examination called the Multiphasic Health Checkup between 1964 and 1973.

As part of the examination, the participants answered detailed questions about their health behaviors and medical histories, and had their height, weight and blood pressure recorded. Researchers were able to determine whether people had suffered from depression based on the self-reported information. The researchers then looked at the same people again between 1994 and 2000 to see if they were depressed in older age. Some years later, between 2003 to 2009, when the average age of the participants was 81, the researchers followed up to see whether they were diagnosed with dementia or Alzheimer’s disease.

The study found that 14.1% of study participants had midlife depression only, 9.2% had depression only in late life, and 4.2% were depressed during both life stages. During the final six years of follow-up, 22.5% of patients were diagnosed with dementia, 5.5% were diagnosed with Alzheimer’s disease and 2.3% were diagnosed with vascular dementia — a type of dementia resulting from brain damage due to impaired blood flow to the brain. (By contrast, Alzheimer’s disease is caused by protein deposits that interfere with brain function.)

Overall, compared with people who had never been depressed, those who had depressive symptoms in middle age (but not later in life) were about 20% more likely to develop dementia later on. People who became depressed in later life were even worse off: they were 70% more likely to develop dementia than their non-depressed peers.

Further, people with late-life depression were twice as likely to have Alzheimer’s disease as those who were depression-free, and those with both midlife and late-life depressive symptoms had more than a three-fold increase in vascular dementia risk.

Because of its observational nature, the study could not firmly establish a causal association, but the findings do suggest that depression precedes vascular dementia. “The people who had depression in their mid- and late-life had an increased risk of developing vascular dementia, and [the depression] could be a true causal risk factor,” says Barnes.

She notes that it’s possible that vascular changes in the brain attributable to depression — particularly in those who have chronic depression — may increase later dementia risk. “These ongoing vascular problems are probably why they had increased risk of vascular depression,” she says.

As far as the link with Alzheimer’s disease is concerned, however, Barnes says depression may more likely be an early symptom, a part of the overall neurodegenerative process that leads to memory loss. “Some of the neurons in the brain that are being influenced could deal with memory and cognitive functions, but some might also be related to mood changes,” says Barnes.

The authors say that further research is needed to confirm their findings, and they acknowledge that the current study had some weaknesses: for one thing, midlife depression was assessed using a single question on a questionnaire. The dementia diagnoses were also based only on reported symptoms and medical histories and did not involve brain imaging or tests of spinal fluid. The researchers also did not look at depression history prior to midlife nor did they take into account the influence of genetic factors on Alzheimer’s disease.

The authors are hopeful that continued research will explore all of these unanswered questions and, most importantly, determine whether treating depression in midlife can help stave off later dementia. It’s a difficult area of research since it is unethical not to treat someone with reported depression and thus hard to find comparisons.

“One of our take home messages is that depression in older adults is not something that should be ignored,” says Barnes. “Depression is not a normal part of aging. … Depression can be devastating by itself, but it can also be associated with increased risk of developing dementia and it is likely to a precursor to dementia. Older adults should be followed a little closer to see if they develop these impairments and depression.”